This invention relates to a controlled release oral pharmaceutical composition and more particularly to a unit dosage that upon administration releases an active agent in a time-controlled fashion.
Controlled release formulations may be formulated with following aspects in mind:
a) the time until the release of active agent (lag time or delay time)
b) the rate of release of active agent (fast or slow)
c) the duration of release of active agent (long or short)
Such aspects may be observed in standard in vitro dissolution tests, e.g., in water or if desired in body fluids, e.g., artificial gastric juices.
Little has been published on reliable time-controlled release formulations allowing a release at a pre-determined time of a single or repeated doses of active agents. There exists a need for such formulations which are commercially acceptable.
After extensive testing, we have now found that it is possible to produce a pharmaceutical composition capable of releasing at a specific time, i.e., with a time delay or lag time, a pharmaceutical active agent or active agent mixture, e.g., substantially independently of the concentration and type of ions present in the gastrointestinal environment, e.g., hydrogen ions and hydroxyl ions, i.e., independently of pH, phosphate ions, and also independently of enzymes, present into the surrounding body fluid.
The present invention provides in one aspect a pharmaceutical composition comprising a first component comprising a first active agent dose wherein on contact with water (or body fluid) 70 to 95% of said dose is released in water within 3 to 4 hours, and a second component comprising a second active agent dose, a water soluble osmosis inducing agent and a water swellable excipient, said second component having a water (or body fluid) permeable coating which, in use upon penetration by water, ruptures after a certain delay time, e.g., due to the swelling of the swellable excipient, and releases (at a predetermined time) the active agent (hereafter referred to additionally as pharmaceutical compositions of the present invention).
The present invention also provides a pharmaceutical composition comprising
a first component comprising an active agent wherein 70 to 95% of said active agent in first component is released in water within 3 to 4 hours, and
a second component comprising the active agent, a water soluble osmosis inducing agent and a swellable excipient in water, said second component having a coating which, upon penetration by the aqueous fluids, breaks after a certain period due to the swelling of the swellable excipient, and releases the active agent at a pre-determined time.
By xe2x80x9cwithin 3 to 4xe2x80x9d hours is meant that at the end of a period of 3 to 4 hours the specified dose of active agent, e.g.,  greater than 80% or  greater than 85%, has been released.
The active agent may be a single active agent or may be a mixture. The active agent may be the same in the first and second doses or different in each dose. Preferably the active agent is the same.
In one embodiment, the coating for the second component is a film, e.g., semi-permeable membrane. The swellable excipient swells in presence of water or body fluid which penetrates through the coating and creates mechanical pressure within the second component thereby causing the coating to rupture or break and the system to open, e.g., like a lid of a box. Also, the swellable excipient may act as an osmotic agent drawing the water into the second component. The thickness of the coating is one of the parameters that controls the time delay, with more coating resulting in a longer time delay.
It will be appreciated that the term xe2x80x9crupturexe2x80x9d preferably refers to breaching but it may also refer to any film system which rapidly (e.g. over 30 minutes or less) dissolves or disappears or changes its properties to permit egress of the active agent.
In another aspect there is provided a controlled release formulation, e.g., the second component, for releasing an active agent dose after a lag time wherein the active agent is released 6 to 12 hours, e.g., 8 hours, after ingestion.
The second component may be coated with two films. A first film is directly in contact with the second component and is preferably a semi-permeable membrane. The second film may be a semi-permeable (e.g., allowing the passage of e.g. water or active agent in one direction) or permeable. The films used in this embodiment may be, e.g., 2 to 5 times, thinner than the one used in a one-film embodiment. Such a composition may provide if desired longer delay times for the second component with a good release of the second dose of active agent. It further provides certain advantages as, e.g., reducing the amount of coating used.
By xe2x80x9cfirst componentxe2x80x9d is meant a component capable of releasing immediately or in a controlled manner, e.g., sustained release, a first therapeutically effective dose of active agent when said first component is put in contact with water or body fluids.
By xe2x80x9csecond componentxe2x80x9d is meant a component capable of releasing immediately or in a controlled manner, e.g., sustained release, a second therapeutically effective dose of active agent when said second component is contacted to water or body fluids.
By xe2x80x9csemi-permeable membranexe2x80x9d is meant a membrane suitable for the passage of the water (or body fluid) into an active agent containing core which is coated with said membrane and hinders egress of a dissolved active agent out of the core.
By xe2x80x9cfilmxe2x80x9d, xe2x80x9cfilm-coatingxe2x80x9d or xe2x80x9cmembranexe2x80x9d is meant, unless stated otherwise, a coating which is applied onto a core component, e.g., the first or second component.
By xe2x80x9cdelay time or lag timexe2x80x9d is meant the duration of time between administration of the composition and the release of an effective dose of active agent from the first or second component.
A person skilled in art will appreciate that various plasma profiles may be obtained by varying, e.g.:
the composition of the first and/or second components, e.g., the nature and amount of excipients and/or active agent(s)
the delay time
the type of semi-permeable and/or non semi permeable membrane
the speed and nature of the active agent release onset (e.g. fast, slow, exponential, logarithmic, linear), which may depend on the rate of rupture of the membrane.
The composition according to the invention may be used for administrating a wide variety of active agents.
The composition according to the invention is suitable for example for water-soluble and also water-insoluble, solid, pharmaceutical active ingredients, which may be inorganic or in particular organic active substances, and are to be used in accordance with their indication as analgesics, antipyretics, antirheumatics, sedatives, hypnotic agents, anti-epileptics, depressants and stimulants, anaesthetics, neuroleptic analgesics, antihistamines, antihypertensive agents, anticoagulants, antithrombotic agents, psychopharmacological agents, psycholeptics, chemotherapeutic agents, e.g. antibiotics, sulphonamides, antituberculosis agents (tuberculostatic agents) or also chemotherapeutic agents against tropical infections, diuretics, spasmolytics, cardiovascular agents, e.g. sympathomimetics, antihypertensive agents, cardiac stimulants, e.g. cardiac glycosides and digitaloids, parenteral sugar therapeutics, analeptics acting on the central nervous system, geriatric agents, tonolytics (of striated muscles), anti-Parkinson agents, cytostatic agents, immunosuppressants, tonics and vitamins, according to B. Helwig (Moderne Arzneimittel), 1980.
As antibiotics, penicillin, tetracycline, chlorotetracycline, bacitracin, nystatin, streptomycin, neomycin, polymicin, gramicidin, oxytetracyclin, chloramphenicol, erythromycin, rifampicin, cefazolin, cefoxitin, cefsulodin, cefotiam and mefoxin may be used, and as chemo-therapeutic agents sulfamethazine, sulfamerazine, sulfamethizole and sulfisoxazole may be used, as solid active ingredients for the presentation according to the invention. In addition, e.g. as sedatives and hypnotic agents chloral hydrate, pentabarbital, phenobarnital, secobarbital, codeine and carbromal may be used, and as cardiac glycosides and digitaloids digitoxin and digoxin may be used, and as sympathomimetics epinephrine may be used as the solid active substance in water-soluble form or water-insoluble form.
In particular, antipyretics, analgesics and antirheumatics may be used as the solid active ingredient in the presentation according to the invention in suitable water-soluble form or water-insoluble form, for example propyphenazone, aminophenazone, aspirin (ASA), antipyrine, methyl nifenazine, melaminsulfone, sulfenazone, phenacetin, pentazocine, lactophenin, paracetamol, quinine, flufenamic acid, mefenamic acid, tolfenamic acid, meclofenamic acid, niflumic acid, clonixin or clonixidin, flunixin, ibuprofen, suprofen, ketoprofen, fenoprofen, pirprofen, diclofenac, ibufenac, procticic acid, naproxen, cicloprofen, tolmetin, clopirac, tiaprofenic acid, oxaprozin, fenclozic acid, fentiazac, clidanac, fenclonac, fenoprofen, flurbiprofen, carprofen, sulindac, cinmetacin, fenbuten, etodolac, butifufen.
Most advantageously, psychopharmacological agents may be used as the solid active ingredient in the presentation according to the invention, e.g. neuroleptics, antidepressants, thymoleptics, thymerethical drugs and tranquilisers in water-soluble form or water-insoluble form, such as thioridazine, imipramine, desimipramine, clomipramine, ketimipramine, opipramol, amitriptyline, nortriptyline, reserpine, aromazine, chlorpromazine, fluopromazine, methopromazine, trimeprazine, diethazine, promethazine, aminopromazine, mepazine, pipamazine and maprotiline.
In addition, antihypertensive agents, such as oxprenolol and meloprolol may be used as the solid active ingredient in the presentation.
In a preferred embodiment a composition according to the present invention is used for administering Rivastigmine (Exelon(copyright)) which is useful in the treatment of patients with mild to moderately severe dementia of the Alzheimer type, also known as Alzheimer""s Disease.
Rivastigmine may be administered as the hydrogen tartrate (hta) in unit dosage form, e.g., an immediate release capsule, at a dose of from 0.5 mg to 6 mg twice a day.
Little has been published in detail on Rivastigmine""s biopharmaceutical properties in humans. It is rapidly and completely absorbed. We have found that it is metabolised mainly through hydrolysis by esterases, e.g., acetyl and butyryl cholinesterase and has a plasma half life of 1 hour. It is subject to pre-systemic and systemic metabolism. We now have found that sustained release formulations of Rivastigmine may be produced with advantageous properties, e.g., better tolerability. Suitable test may be effected in fasted beagle dogs.
According to the present invention, Rivastigmine may be used in the form of the free base or a pharmaceutically acceptable salt thereof. Preferably the hydrogen tartrate (hta) is used. The composition of the invention allows, e.g., the manufacture of once a day pharmaceutical oral forms for patients who have to take more than one dose of an active agent per day, e.g., at specific times, so that their treatment is simplified. With such compositions tolerability may be improved, e.g., with Rivastigmine, and this may allow a higher starting dose and a reduced number of dose titration steps.
In a further aspect the invention relates to a pharmaceutical composition comprising rivastigmine adapted so that in use on oral administration a therapeutically effective dose of rivastigmine is released only after 6 hours (hereafter referred to additionally as pharmaceutical compositions of the present invention).
In a further aspect the invention relates to a pharmaceutical composition capable of releasing twice on administration a therapeutically effective dose of rivastigmine at different intervals upon oral administration (hereafter referred to additionally as pharmaceutical compositions of the present invention).
In preferred pharmaceutical composition of the invention, a first therapeutically effective dose of rivastigmine is released within 3 to 4 hours of ingestion and, subsequently, a second therapeutically effective dose of rivastigmine is released 6 to 12, preferably a to 10 hours, after ingestion.
The first component may be produced, e.g., by any conventional methods to provide the desired controlled release characteristics. It may be produced in solid form, e.g., a tablet, (e.g., a matrix-tablet), coated particles (e.g., non-pareilles) or pellets, e.g., coated pellets.
In one embodiment of said first component, the active agent is incorporated in a hydrophilic substance forming a gel substance on contact with water, e.g., which may be present in a ratio of from 10 to 50%, e.g., 15 to 45%, by weight of the first component, e.g., in the form of a controlled release tablet formulation, e.g., a matrix-tablet.
Hydrophilic gel forming substances commonly used in tablet formulations may be used and reference is made to the extensive literature on suitable substances, see in particular Fiedler""s xe2x80x9cLexicon der Hilfstoffexe2x80x9d, 4th Edition, ECV Aulendorf 1996 and xe2x80x9cHandbook of Pharmaceutical Excipientsxe2x80x9d Wade and Weller Ed.(1994) the contents of which are incorporated herein by reference.
Preferred hydrophilic gel forming substances which may be used for the first component include one or more natural, partially or totally synthetic, anionic or, preferably, non-ionic hydrophilic gums, modified cellulose substances or protein aqueous substances such as, for example, acacia, gum tragacanth, locust bean gum, guar gum, karaya gum, agar, peptin, carrageen, soluble and insoluble alginates, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, carboxypolymethylene, gelatin. Preferred are cellulose which include methylcellulose, hydroxypropylcellulose and especially hydroxypropylmethylcellulose and sodium carboxymethylcellulose.
Especially preferred hydrophilic gel forming substances which may be used for the first component comprises high-viscosity hydrophilic swellable substances, e.g. substances having a viscosity in the range of 10,000 to 200,000 mPa-s, e.g. 50,000 to 150,000 mPa-s, e.g., 100,000 mPa-s. A preferred swellable substance which may be used is hydroxypropylmethylcellulose, e.g., Methocel, e.g., K100M (100,000 mPa-s/2% solution in water at 20xc2x0 C.), having a methoxyl content of, e.g., 15 to 30%, e.g., 19 to 24%, and a hydroxypropoxyl content of, e.g., 5 to 15%, e.g., 7 to 12%. Swellable substances with diverse viscosities may be prepared as disclosed in xe2x80x9cHandbook of Pharmaceutical Excipientsxe2x80x9d Wade and Weller Ed.(1994).
The weight portion of hydrophilic gel forming substances in the formulation may be from 10 to 50%, e.g., 25 to 50%, preferably 40%.
Said first component may comprise 3 to 20%, e.g. 5 to 15%, e.g. 6 to 13% by weight of the active agent, e.g., rivastigmine hydrogen tartrate (hta).
It may be also convenient to incorporate in the first component at least one of other soluble or insoluble pharmaceutical excipients as tablet diluents such as calcium sulphate, calcium phosphate, lactose, mannitol, sucrose. For example, microcristalline cellulose in granular powder and/or fine powder may be incorporated e.g. from 10 to 50%. For example, microcristalline cellulose fine powder may be present in a range of 20 to 50%, e.g, 30 to 40% by weight of the first component and microcellulose granular powder in a range of 10 to 40%, e.g., 20 to 30% by weight of the first component.
At least one glidant, e.g., dispersed silicon dioxide, talc, may be present in a range of 0.1 to 1% by weight of the first component and at least one tablet lubricant, e.g., magnesium sterate, steric acid, hydrogenated castor oil, polyetheylene glycol, may also be present in a range of 0.1 to 1% by weight of the first component, preferably 0.5%.
For example, the first component in this specific embodiment may have the following active agent, e.g., rivastigmine, release characteristic in water or artificial stomach juices (e.g. 0.1 N HCl):
In a further embodiment of the first component, the active agent is incorporated in coated particles comprising a diffusion coating. The coating may be adapted to provide the controlled release of the active agent. Coating aids, conveniently used in coating formulation may be used. These coatings may include further binders, lubricants, glidants, stabilising agents, fillers or diluents, surfactants and the like. As disintegrants one can particularly mention CMC-Ca, CMC-Na, crosslinked PVP (Crospovidone, Polyplasdone of Kollidon XL), Alginic acid, sodium alginate and guar gum, most preferably crosslinked PVP, Crospovidine, crosslinked CMC and Ac-Di-Sol.
As binders which may be used in these coatings one can particularly mention polysaccharides, e.g. potato starch, wheat starch, corn starch, hydroxypropylmethylcellulose, e.g., products known under the registered trade marks Avicel(copyright), Filtrac(copyright), Heweten(copyright) or Pharmacel(copyright).
Preferably cores which may be used for the first component are inert and water soluble. Typically the diameter is about 0.5 to 1.5 millimeters.
The coatings which may be used for the first component may comprise for example a cellulose derivative, e.g., which may be applied as a film. Common cellulose coatings may be used and reference is made to the extensive literature on suitable diffusion controlling substances.
As a preferred cellulose coating for the first component, one may use a coating comprising ethyl cellulose and hydroxypropyl methylcellulose (hereafter HPMC).
The ethyl cellulose has preferably a molecular weight 10,000 to 15,000,000, e.g., 50,000 to 1,000,000, e.g., 75,000 to 80,000, Daltons. It is preferably cellulose substituted by ca 2 to 3 ethoxy groups per unit saccharide. Preferably it has an ethoxy content of 44-51%.
Ethyl cellulose as used in the examples preferably is ethyl cellulose N10 Brand Aqualon(copyright) N10 (available from Dow Chemicals Company).
Hydroxypropyl methyl cellulose has preferably a viscosity of from 1 to 10 cps, e.g., 2 to 8 cps. Preferably it has a molecular weight of from 10,000 to 1,500,000 Daltons, e.g., 100,000 to 1,000,000, e.g., 300,000 to 800,000. It is preferably cellulose substituted by ethyl and hydroxypropyl groups.
Hydroxypropyl methyl cellulose preferably has a viscosity of 3 cps or 5 cps.
The particles may have a diffusion coating preferably comprising ethyl cellulose and hydroxypropyl methylcellulose, e.g., in a ratio of from 15:1 to 1:1, e.g., from 9:1 to 1:1, e.g., from 8:1 to 2:1, e.g., from 7:1 to 3:1.
The particles may have a drug (active agent) coating preferably comprising hydroxypropyl methylcellulose. The drug coating may contain about 50 to 90% by weight of said active agent, e.g., rivastigmine, for example from 50 to 80% by weight of rivastigmine. The amount of drug may comprise, e.g., 3-15% of the core.
Typically, the drug coating to diffusion coating ratio is from 3:1 to 1:1.
If desired a protective coating may be present between the diffusion coating and the drug coating. It may comprise hydroxypropylmethylcellulose or ethyl cellulose. The protective coating/diffusion coating ration may be, e.g., from 1:1 to 1:10, e.g., from 1:2 to 1:8.
Silica may be present, e.g, in 70% by weight of the film coating.
For example, the first component in this specific embodiment may have one or more, e.g., all of the following active agent, e.g., rivastigmine, release characteristic in water or artificial stomach juices (e.g. 0.1 N HCl):
As a further example, the first component in this specific embodiment may have the following active agent, e.g., rivastigmine, release characteristic in water or artificial stomach juices (e.g. 0.1 N HCl):
In a further embodiment of the first component, the active agent is incorporated into pellets, e.g. extruded pellets, which may be coated with a diffusion coating as previously described. The pellets may comprise the active agent, e.g., rivastigmine, in the same form as for the particles. It may further comprise binders as those mentioned above and diluents as calcium sulphate, calcium phosphate, lactose, mannitol or sucrose.
For example, the first component in this specific embodiment may have one or more, e.g., all of the following active agent, e.g., rivastigmine, release characteristics in water or artificial stomach juices (e.g. 0.1 N HCl):
It may have preferably the following release characteristics:
The present invention further relates to a controlled release oral pharmaceutical composition comprising a therapeutically effective dose of Rivastigmine and pharmaceutically acceptable excipients, e.g., the first component (hereafter referred to additionally as pharmaceutical compositions of the present invention).
The present invention further relates to a controlled release oral pharmaceutical composition comprising a therapeutically effective dose of Rivastigmine wherein in use 50 to 95%, e.g., 50 to 80%, 60 to 90%, 70 to 95%, of rivastigmine is released in water or body fluids, e.g., artificial stomach juices within 3 hours (hereafter referred to additionally as pharmaceutical compositions of the present invention).
The delay time for the second component may be determined precisely, e.g.,
by the type and amount of water soluble excipients in the core
by the water permeability and the number of film(s) coated on the second component
by the mechanical strength, i.e., elasticity and tearing strength, of the film,
by the type and amount of swellable excipient incorporated in the core.
An appropriate coating for the second component may be a semi-permeable membrane which is adapted to allow in use the passage of water (in use gastro-intestinal juices) into the core and to hinders egress of the dissolved active agent out of the core.
Water is drawn through the semi-permeable membrane at a rate which may be controlled by the composition of the membrane. The water which has penetrated the core dissolves at least part of the active agent. Osmotic pressure is thereby produced. The greater the pressure, the more molecules or ions go into solution, until under normal circumstances a saturated solution is produced.
In one embodiment, upon penetration by water or body fluid, the osmotic pressure, which as a consequence also induces swelling of the swellable excipient, may be produced by the active agent, e.g., rivastigmine, itself. However, a carrier which is soluble in water may be added in order to produce the necessary osmotic pressure. In this way, the osmotic pressure necessary for inducing the operating principle of the second component can be attained in such a way that the body fluid entering to balance the osmotic gradient produces the desired swelling of the swellable excipient (disintegrant) and after a certain delay time the rupturing or breaking of the film coating allows the release of the active agent. By optionally adding a water-soluble carrier in the core of the tablet, the second component may be produced in almost pH-independent form, i.e., independent of the concentration of hydrogen ions and hydroxyl ions and/or independent of other ions, such as phosphate ions, and also enzymes, for example in the alimentary tract.
Appropriate semi-permeable membranes for the film layer include the semi-permeable membranes described in literature, for example in U.S. Pat. Nos. 3,916,899 and 3,977,404, which are suitable for passage of the water (body fluid) and not the dissolved active agent and are thus suitable for bringing about osmosis. For example, artificially produced membranes may be used, which consist of cellulose acetate, cellulose triacetate, agar acetate, amylose acetate, cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylamino acetate, cellulose acetate ethyl carbonate, cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate methyl sulphonate, cellulose acetate butyl sulphonate, cellulose ether, cellulose acetate propionate, cellulose acetate diethylamino acetate, cellulose acetate octate, cellulose acetate laurate, methyl cellulose, cellulose acetate-p-toluenesulphonate, hydroxylated ethylene vinyl acetate, cellulose acetate butyrate and of other cellulose acetate derivatives. Other appropriate semi-permeable membranes are also hydroxypropylmethyl cellulose and polymeric epoxides, copolymers of alkylene oxide and alkyl glycidyl ether, polyglycols or polylactic acid derivatives and further derivatives thereof. In addition, mixtures may also be used, e.g. of water-insoluble acrylates, e.g., copolymer of ethyl acrylate and methyl methacrylate.
Generally, all semi-permeable membranes which are known from literature and have water-permeable properties are suitable for producing the film for the second component.
Coating of, e.g., tablets, e.g., compressed tablets, core particles or pellets, with a film comprising, e.g., a semi-permeable membrane of required thickness, may be effected in fluidised beds, coating pans or coating may be effected using, e.g., tabletting machines (dry coated tablet).
The second component may for example also be contained in a capsule, e.g., a gelatin capsule, which contains the active agent, e.g., rivastigmine, a swellable excipient, optionally a water-soluble carrier and other excipients, such as lubricants and sustained release agents in powder form, and is coated with the semi-permeable membrane as a film.
Appropriate films which may be used as a second coating for the second component include membranes which may be permeable or semi-permeable to water or body fluid, e.g., sustained release membranes, as described in literature. This second film-coating may be applied in the same manner as for the first film.
A preferred second film-coating for the second component comprises ethylcellulose, e.g. Ethylcellulose Brand Aqualon(copyright) N10 (available from Dow Chemicals Company). It may be applied, e.g., by spraying a solution comprising Ethylcellulose and HPMC 5 cps in a weight ratio of from e.g., 15:1 to 1:1, e.g., 9:1 to 1:1, e.g., from 8:1 to 2:1, e.g., from 7:1 to 3:1.
The ethyl cellulose has preferably a molecular weight 10,000 to 15,000,000, e.g., 50,000 to 1,000,000, e.g., 75,000 to 80,000, Daltons. It is preferably cellulose substituted by ca 2 to 3 ethoxy groups per unit saccharide. Preferably it has an ethoxy content of 44-51%.
Hydroxypropyl methyl cellulose has preferably a viscosity of from 1 to 10 cps, e.g., 2 to 8 cps, preferably 3 cps or 5 cps. Preferably it has a molecular weight of from 10,000 to 1,500,000 Daltons, e.g., 100,000 to 1,000,000, e.g., 300,000 to 800,000. It is preferably cellulose substituted by ethyl and hydroxypropyl groups.
In a preferred embodiment, the weight ratio between the first and the second film applied on the second component is 20:1 to 1:5, e.g., 15:1 to 1:1, e.g., 10.1 to 2:1.
In a preferred embodiment of the invention, the film thickness for the second component may be in a range of from 50 to 800 micrometers (em), e.g., 100 to 600 xcexcM. For a second component having one film a preferred thickness is in the range of from 300 to 500 xcexcm, e.g., 350 to 400 xcexcm. For a second component having two films a preferred thickness is in the range of from 100 to 300 xcexcm, e.g., 150 to 200 xcexcm.
The nature and the amount of the excipients and the active agent of the second component (excluding film-coating(s) to be ruptured) may the same or not as the first component.
Suitable swellable excipients or disintegrating agents for the second component may be inert substances which swell rapidly upon contact with aqueous liquids, e.g., alginic acid and derivatives, agar-agar, cellulose such as microcrystalline or microfine cellulose, methyl cellulose, crosslinked carboxymethyl cellulose, carboxymethyl starch, modified starch, crosslinked polyvinyl polypyrrolidone, Colloidal silicon dioxide, high molecular weight polymers comprising ethylene oxide, bentonite, Veegum, montmorillonite, dried citrus pulp, xylans and also cationic and anionic exchangers such as cholestyramines.
Further excipients may be used to produce or induce the osmosis in the swelling process in the second component are water-soluble carriers (osmosis-inducing substances), e.g., substances that do not irritate the gastric or intestinal mucous membranes, e.g. inorganic or organic salts such as sodium chloride, sodium hydrogen phosphate, sodium nitrate and sodium acetate, or also acids such as tartaric, citric or also succinic acid and also sugars, especially e.g. mannitol, glucose, fructose, lactose and dextran compounds with different molecular weights. The amount of carrier may vary from a fragment to many times the quantity of rivastigmine employed.
The lubricants which may be an optional further excipient for the second component may be e.g., magnesium stearate, silicon aerogel, talc, stearic acid, hydrogenated castor oil, polyethylene glycol (PEG).
Optional additives for the second component may be, e.g., anti-oxidants, e.g, a-tocopherol or butylated hydroxytoluene (BHT).
Optional additives in film coating for the second component may be, e.g., pigments such as coloured iron oxides or titanium dioxide and/or flavourings, e.g., sweeteners, e.g., saccharine, Na cyclamate or sugar.
A preferred second component comprises, e.g., (weight%):
The invention further relates to a pharmaceutical composition comprising a core coated with two films, the first inner film being a semi-permeable to water or body fluids film applied directly on said core and comprising cellulose acetate, e.g., cellulose acetate E320 or 398-10, the second outer film being a permeable to water or body fluids film comprising ethylcellulose, e.g., Ethylcellulose N10.
The cores in question, comprising the active agent, e.g., rivastigmine, and excipients, e.g., may be the compressed tablets, capsules and pellets that are usual in galenics and may be produced by known processes. For example, the tablet mass may be produced by mixing the active agents disintegrant and optional further excipients, such as carriers, lubricants and if desired also sustained release excipients as required. Production of the compressed tablets and pellets may be effected, e.g., using the tabletting machines which are known for the preparation of for example round and rod-shaped compressed tablets and pellets, and the capsules are filled using known capsule filling machines.
The sustained release excipients that are used may be essentially water-insoluble excipients or mixtures thereof, e.g., lipids, inter alia fat alcohols, e.g. cetyl alcohol, stearyl alcohol and cetostearyl alcohol; glycerides, e.g. glycerin monostearate or mixtures of mono, di- and triglycerides of vegetable oils; hydrogenated oils, such as hydrogenated castor oil or hydrogenated cottonseed oil; waxes, e.g. beeswax or carnauba wax; solid hydrocarbons, e.g. paraffin or mineral wax; fatty acids, e.g. stearic acid; certain cellulose derivatives, e.g. ethyl cellulose or acetyl cellulose; polymers or copolymers, such as polyalkylenes, e.g. polyethylene, polyvinyl compounds, e.g. polyvinyl chloride or polyvinyl acetate, as well as vinyl chloride-vinyl acetate copolymers and copolymers with crotonic acid or polymers and copolymers of acrylates and methacrylates, e.g. copolymers of ethyl acrylate and methyl methacrylate.
A person skilled in the art may use other excipients than those disclosed above to obtain the desired effect. Reference is made to the extensive literature on suitable excipients provided in the art in particular Fiedler""s xe2x80x9cLexicon der Hilfstoffexe2x80x9d, 4th Edition, ECV Aulendorf 1996 and xe2x80x9cHandbook of Pharmaceutical Excipientsxe2x80x9d Wade and Weller Ed.(1994) the contents of which are incorporated herein by reference.
As already stated initially, the release which is to be effected at different time intervals may be controlled precisely by the composition and the layer thickness of the coating (film) used for the second component, mechanical strength and elasticity and optionally through the quantity and swelling property of the swelling or disintegrating agent.
The second component, e.g., with one film, according to the invention may have one or more, e.g., all of the following release characteristics in water:
The second component, e.g., with two films, according to the invention may have one or more, e.g., all of the following release characteristics in water:
The rupture time may lead to 85% or more, e.g., 90%, of the active agent in the second component released within 30 minutes.
The pharmaceutical composition according to the invention preferably comprises from 0.5 to 25%, e.g., 1 to 10%, e.g., 2 to 5%, by weight of rivastigmine of the total composition.
The pharmaceutical compositions of the present invention are useful in the known indications of the particular active agent incorporated therein.
The exact amounts of active agent doses and of the formulation to be administered depend on a number of factors, e.g., the condition to be treated, the desired duration of treatment and the rate of release of active agent.
For example, the amount of the active agent required and the release rate thereof may be determined of the basis of known in vitro or in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.
For example, for rivastigmine, dosages in the range of 1 mg to 12 mg of active agent per day for a 70 or 75 kilogram mammal, e.g., humans, and in standard animal models, may be used. A surprisingly increased tolerability of rivastigmine provided by the compositions may be observed in standard animal tests and in clinical trials.
The pharmaceutical compositions of the invention are, e.g., administered, e.g., orally once-a-day, if two active agent doses are present and twice-a-day if a second active agent dose is present.
In a further aspect, the present invention provides the use of an active agent, e.g., rivastigmine, and excipients as defined above in the manufacture of a medicament for a once-a-day treatment of patients with, e.g., mild to moderately severe Dementia of the Alzheimer""s type by oral administration.
In the following non-limitative examples, the invention is more fully clarified. If not otherwise stated, the parts are parts by weight. Temperatures are given in degrees Celsius.
The first component may be produced in conventional mariner by mixing the components. Below are examples of specific forms of first component allowing various release profile of the active agent contained therein.